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Biomedical subjects

H B Jones

Publications and source records attributed to H B Jones.

At least 55 records · Page 3Linked to original sources
PubMed1988

Red cell haemolysis induced by SK&F 95018--a combined vasodilator and beta-adrenoceptor antagonist.

SK&F 95018, a potential antihypertensive agent with the combined properties of vasodilation and beta-adrenoceptor antagonism, induced red urine when given intravenously to a dog. Further studies revealed that in the dog, SK&F 95018 treatment led to haemoglobinaemia, haemoglobinuria and a fall in the red blood cell count. The compound was therefore suspected of causing red cell haemolysis and this was confirmed using dog blood in an in vitro haemolysis test system. Oral administration of the compound to dogs gave no indication of haemolysis, but the animals lost large portions of their dose through vomiting and the lack of effect is therefore questionable. Rats, which have no vomit reflex, were treated orally and although no direct evidence of haemolysis was obtained (e.g. haemoglobinaemia), the presence of polychromasia suggested some loss of mature red blood cells had occurred. Rat blood was haemolysed in vitro by SK&F 95018. Human red cells were also used in the in vitro haemolysis test system and these, too, were lysed by the compound. The haemolysis was shown to be related to the structure of the compound itself rather than to its pharmacological effects and development of SK&F 95018 as an antihypertensive agent was abandoned. Electron microscopy indicated that SK&F 95018 induced alterations in the red cell membrane which led to shape change, characterized by discocyte to spherocyte transformation, and finally haemolysis. The mechanism of this effect remains under investigation.

Administration, Oral↗
PubMed1987

The mechanism of acute cytotoxicity of triethylphosphine gold(I) complexes. I. Characterization of triethylphosphine gold chloride-induced biochemical and morphological changes in isolated hepatocytes.

Triethylphosphine gold complexes are effective therapeutic agents used for the treatment of rheumatoid arthritis. Many of those molecules are also highly cytotoxic in vitro and can inhibit DNA and protein synthesis. Preliminary experiments have indicated that triethylphosphine gold chloride (TEPAu) may induce the peroxidative decomposition of cellular membrane lipids. The purpose of these investigations therefore was to evaluate the role of lipid peroxidation in the mechanism of acute cytotoxicity of a gold(I) coordination complex, TEPAu, and to examine the early morphological and biochemical changes induced by TEPAu in suspensions of freshly isolated rat hepatocytes. TEPAu caused a rapid loss of cell viability at concentrations above 25 microM which was significantly different from that of control by 60 min and complete by 180 min of incubation. TEPAu also depleted cells of reduced glutathione (GSH) and increased the formation of malondialdehyde (MDA) by 60 min. Incubation of cells with either of the antioxidants, N,N'-diphenyl-p-phenylenediamine (DPPD) or promethazine blocked the formation of MDA but did not alter the time course of cell death or GSH depletion induced by TEPAu. TEPAu also caused a decrease in cellular NADPH and NADH by 10 min. Electron microscopy of hepatocytes exposed to TEPAu revealed early (5 min) formation of flocculent electron-dense precipitates within condensed mitochondria. These changes characteristically preceded cell death. Energy-dispersive electron-probe microanalysis indicated that the electron-dense precipitates did not contain detectable amounts of gold. TEPAu also caused a concentration-dependent decrease in cellular ATP and oxygen consumption in isolated rat hepatocytes. These data suggest that lipid peroxidation, as indicated by the formation of MDA, is probably not a major mechanism by which triethylphosphine gold complexes lethally injure cells. These data, therefore, suggest that mitochondria may be target organelles in TEPAu-induced toxicity to isolated rat hepatocytes.

Animals↗
PubMed1986

The axon reaction in spinal ganglion neurons of acrylamide-treated rats.

Rats were given acrylamide in doses of either 30 or 50 mg/kg (5 days each week) for up to 3 weeks and killed at weekly intervals. The right sciatic nerve was tied tightly at the level of the major trochanter 4 days before killing the animals by perfusion fixation when ipsilateral and contralateral sensory ganglia (L5 and L6) were removed. The effects on neuronal perikarya of axotomy alone, of acrylamide alone and of these combined were studied by light and electron microscopy. The responses to axotomy and to acrylamide intoxication shared certain features, namely peripheral Nissl substance and to a lesser degree nuclear eccentricity, nucleolemmal crenation and mitochondrial enlargement. Neurofilament loss was present only with acrylamide. In combined axotomy and acrylamide all these five features were prominent. These findings indicate firstly that the individual responses to axotomy and to acrylamide, while sharing several features, are subtly different and secondly that acrylamide appears to impede the vital neuronal responses directed towards repair of the axon.

Acrylamide↗
PubMed1985

Acute toxicity and recovery in the hemopoietic system of rats after treatment with ethylene glycol monomethyl and monobutyl ethers.

Male rats were given ethylene glycol monomethyl ether (EGM) or ethylene glycol monobutyl ether (EGB) po for 4 consecutive days at doses of 100 or 500 mg/kg body wt/day for EGM, and 500 or 1000 mg/kg body wt/day for EGB. Animals were killed on Days 1, 4, 8, and 22 after the final treatment. Both EGM and EGB produced thymic atrophy and lymphocytopenia and, in the case of EGM, neutropenia also. Hemolytic anemia induced by EGB resulted in splenic extramedullary hemopoiesis, hyperplasia of both spleen and bone marrow, and reticulocytosis. Apart from residual slight increases in spleen weight, mean red cell volume, and mean corpuscular hemoglobin at the end of the recovery period, other effects were reversible. With EGM, reduction in the numbers of circulating red cells was only slight. Treatment with EGM also abolished splenic extramedullary hemopoiesis which partially recovered on Day 4, followed by a marked response on Day 8, and return to the moderate control values on Day 22. Femoral bone marrow was hemorrhagic 1 day after treatment with EGM which appeared to be associated with sinus endothelial cell damage. By Day 4 the histologic appearance of the marrow was normal. Testicular atrophy was also produced in EGM-treated animals which persisted for the duration of the experiment. It is concluded that EGM and EGB differ considerably in the spectrum of toxic changes induced, and apart from testicular atrophy, these changes were largely reversible within a short time of the end of treatment.

Animals↗
PubMed1984

X-ray microanalysis of liver and kidney in copper loaded sheep with and without thiomolybdate administration.

The distribution of elements in the cells of the liver and kidney of normal sheep, of sheep chronically intoxicated with copper and in sheep given copper and thiomolybdate was studied by atomic absorption spectrophotometry, electron microscopy and electronprobe X-ray microanalysis. Copper concentrations were increased in the liver and kidney during the pre-haemolytic and haemolytic stages of the disease. In addition iron concentrations were markedly increased in the kidney during haemolysis. Copper and molybdenum concentrations were increased in the kidney of sheep receiving copper and thiomolybdate or thiomolybdate alone. By electronprobe X-ray microanalysis at the pre-haemolytic and haemolytic stages, copper together with small amounts of calcium and chromium were found in lysosomes of liver cells. In addition, in animals killed during haemolysis, high concentrations of iron were found in apical lysosomes of kidney proximal tubule cells. Copper and molybdenum were found in apical lysosomes of kidney tubule cells in animals given copper and thiomolybdate or thiomolybdate alone. The accumulation of copper with molybdenum and sulphur in the lysosomes of thiomolybdate treated copper intoxicated animals was demonstrated for the first time and may indicate the sequestration within lysosomes of a copper-molybdenum-protein complex.

Animals↗
PubMed1983

Distortions of the nodes of Ranvier from axonal distension by filamentous masses in hexacarbon intoxication.

A study has been made of the structural changes of nodal and paranodal regions of the nodes of Ranvier of peripheral nerves of rats in which marked accumulations of neurofilaments have occurred within axons under the influence of 2,5-hexanediol over 10 weeks. The neurofilamentous masses caused distension of the axon at two points of apparent weakness as they attempted to slide through the axonal constriction at the nodes. Principally, a spiral axonal protrusion pushed into the zone of unattached myelin loops in the proximal paranodal spinous bracelet of Nageotte. This led to a conical widening of the paranodal constriction and considerable attenuation of the overlying myelin. No degeneration of the myelin occurred however. Alternatively, or additionally, a protrusion occurred of the axon at the nodal region which increased the nodal gap width and occasionally compressed and displaced the adjacent distal paranodal constriction which could have led to some obstruction of axoplasmic flow. Swelling of distal paranodal regions occurred later and was usually associated with proximal swelling. It was also accompanied by evidence suggesting transnodal passage of filamentous material. Sometimes, however, striking nodal constriction occurred in association with symmetrical paranodal swelling. These observations suggest that the spiral glial-axonal relationships at nodes of Ranvier are capable of marked deformation that might allow the intra-axonal neurofilamentous masses to move distally. These findings are discussed in relation to the structural features of the paranodal constrictions.

Animals↗
PubMed1983

Cytochemical staining characteristics of peripheral nodes of Ranvier in hexacarbon intoxication.

Changes in the distribution of stainable gap substance and subaxolemmal density at peripheral nodes of Ranvier in hexacarbon-intoxicated rats have been studied by light and electron microscopy. Cupric ion binding to the nodal gap substance was seen in normal nodes as a discrete annulus by the formation with ferrocyanide of Hatchett's Brown reaction product. Staining of osmicated fibres with ferrocyanide ions alone gave a deposit of black reaction product at the subaxolemmal region at nodes of Ranvier. Paranodal distension by neurofilamentous masses and separation of the terminal myelin loops in the early phase of paranodal dilatation produced no change in the distribution of the two kinds of stainable material. Paranodal myelin retraction with increases both in nodal gap width and nodal axon diameter resulted in displacement and attenuation of both stained regions. Axonal protrusion at the nodal region tended only to displace the stained gap substance, but sometimes it resulted in its attenuation. Occasionally loss of subaxolemmal staining was found. The possible functional relevance of these abnormal findings is discussed in relation to changes in conduction in affected nerves.

Animals↗
PubMed1982

Recovery from 2,5-hexanediol intoxication of the retinotectal tract of the rat. An ultrastructural study.

Rats were given 2,5-hexanediol, a metabolite of n-hexane, in the drinking water until they developed a marked degree of paresis over about 7 weeks and were then allowed to recover naturally. The time course and the manner of removal of the neurofilamentous masses accumulated within axons caused by the intoxication were followed by electron microscopy over the subsequent 8 weeks. The neurofilamentous masses slowly disappeared completely from the axons of this tract, without there being any degeneration, over 6-7 weeks. They disappeared first from the fibres in the brachium of the superior colliculus, perhaps by transport towards the terminals, and later from the axons within the superior colliculus itself. Particularly in preterminal fibres in the superior colliculus the filamentous accumulations became permeated by a network of smooth endoplasmic reticulum which may have played a part in the removal of the filaments. Accumulations of mitochondria and dense bodies in preterminal regions, presumed to be caused by obstruction to retrograde transport, disappeared pari passu with loss of the filaments. The significance of these events in relation to neurofilament metabolism is discussed.

Animals↗